Varicella-zoster virus (VZV) is an ancient virus. Estimations of its origins have established that the modem herpesviruses arose some 60-80 million years ago. VZV is a member of the alphaherpesvirus subfamily of herpesviridae. It is the etiologic agent of chickenpox in childhood, after which the virus enters a latent state in the dorsal root ganglia; decades later, the same virus reactivates and causes the disease shingles (herpes zoster). The entire sequence of the 125 kbp VZV genome has been published (see Davison et al., J. Gen. Virol., 67:1759-1816 (1986)). With the subsequent publication of sequence data from other herpesviruses, the alphaherpesviruses have now been subdivided into two genera called Simplexvirus and Varicellovirus. VZV is considered to have one of the most stable genomes of all herpesviruses. The Oka strain of varicella vaccine derived from a Japanese child with chickenpox has a few minor genomic differences from North American strains, but to date no antigenic variation has been discovered amongst the major surface immunogens of the virion (Arvin et al., Annu. Rev. Microbiol., 50:59-100 (1996)).
Based on their extensive analyses of herpesviral molecular evolutionary history, it has been estimated that herpesvirus DNA sequences mutate 10-100 times faster than the equivalent classes of sequences on the host genome. For glycoprotein gB, a highly conserved open reading frame (ORF) among all herpesviruses, it has been calculated that nonsynonymous substitutions have occurred at a rate of 2.7×10−8 substitutions per site per year and synonymous substitutions at 10−7 substitutions per site per year. Convincing arguments have been made in favor of the concept of cospeciation; in other words, herpesvirus lineages arise by way of co-evolution with their specific host. In the case of VZV, the progenitor virus most likely arose 60-70 million years before the present.
Of all the human herpesviruses, VZV may undergo the fewest replication cycles during the lifetime of the infected host. Based on a probable schema of pathogenesis, the virus actively replicates for a period of 10-14 days after infection of the human host. During a bout of chickenpox, therefore, VZV has at most 20 replication cycles. Based on the current understanding of VZV latency and reactivation, no further replication occurs unless the individual develops herpes zoster in late adulthood. Because of the above scenario, the genetic stability of the VZV genome has been presumed.
VZV contains the smallest genome of the human herpesviruses, containing about 70 ORFs within the complete VZV-Dumas sequence. Of these ORFs, at least seven code for glycoproteins, of which glycoprotein B (gB), glycoprotein E (gE), glycoprotein H (gH), and glycoprotein I (gI) are present on the exterior of the virion. VZV gE, in complex with glycoprotein I (gI), acts as a human Fc receptor on the surface of infected cells (Litwin et al., J. Virol., 66:3643-51 (1992), Litwin et al., Virology, 178:263-72 (1990)). The cytoplasmic tails of both gE and gI contain endocytosis motifs, allowing internalization and recycling of the complex to and from the cell (Olson et al., J. Virol., 71:110-119 (1997), Olson et al., J. Virol., 71:4042-4054 (1992)). The gE and gI cytoplasmic tails also are modified by both serine/threonine and tyrosine phosphorylation motifs. The fact that gE cannot be deleted suggests that it is essential (Cohen et al., Proc. Natl. Acad. Sci. USA, 90:7376-7380 (1993), Mallory et al., J. Virol., 71:8279-88 (1997)).
In VZV infection in humans, VZV gE is the most abundantly produced viral glycoprotein during infection. VZV gE is a major antigenic determinant to which numerous humoral and cytolytic responses are observed (Arvin et al., J. Immunol., 137:1346-1351 (198); Bergen et al., Viral Immunol., 4:151-166 (1991); and Ito et al., J. Virol., 54:98-103 (1985)). Recently, an immunodominant B-cell epitope was demarcated in the gE ectodomain; the epitope is defined by murine monoclonal antibody (MAb) 3B3 (Duus et al., J. Virol., 70:8961-8971 (1996); Hatfield et al., BioTechniques 22:332-337 (1997); and Grose, U.S. Pat. No. 5,710,248).
It has long been believed that varicella zoster virus exists in nature as a single serotype (Rentier, Neurol., 45(Suppl. 8), S8 (1995), and that all varicella zoster viruses had essentially the same immunological properties. The first strain of varicella zoster virus that was sequenced was VZV-Dumas. Following the publication of this sequence, it was further believed that all varicella zoster viruses had essentially the same genetic properties as VZV-Dumas.
Significant progress has been made in the diagnosis of and vaccination against the sole VZV serotype that is believed to exist and cause disease in the United States. However, the production of the reagents used in diagnosis and vaccination of VZV is time consuming and expensive due to the slow growth rate of the strain grown to produce antigens for diagnostic and vaccine use.